As haematologists, we always seek to follow standardised guidelines for practice and apply the best treatment for our patients with blood diseases within our means. However, treatment can never follow an exact recipe. Opinions differ as to the best approach; sometimes more than one treatment approach results in identical outcomes, or treatments differ only by the manner in which they fail. Furthermore, the haematologist is faced with constraints relating to the local economic environment. Patients too are not the same the world over. Early presentation is commoner in the developed world, as is the patient's understanding of the disease process. This in turn has an impact on the way patients are managed, the rigorousness of patient adhesion to the treatment schedule and the outcome. For these reasons, given the same starting conditions, patients will be treated differently according to the institute and the country they are in. In this series of global views, I have tasked experts from around the world to describe their management plan and rationale for a specific disease presentation. Here they explore the management of myeloproliferative neoplasms (MPNs) in five different institutions worldwide balancing health systems in widely varying health systems. We finish with a conclusion from an expert in the field comparing and contrasting these different management styles and considering their merits and limitations. The case history and questions posed to the experts are shown in the Boxes 1 and 2, and their responses are summarised in Table 1. FBC, SBP, se-EPO. JAK mutation panel. BM biopsy. Phlebotomy and ASA 80 mg orally/day. Follow-up every 2–4 weeks initially; every 3 months once stabilised plus maintenance phlebotomy. FBC, SBP, se-EPO, BM aspiration. JAK2 V617F and JAK2 exon 12 mutations. Abdominal ultrasound. Assessment of symptom burden using MPN-10 scoring. Red blood cell apheresis. ASA 100 mg orally/day. IFNα (≤60) or HU. FBC, SBP, se-EPO. JAK2 V617F (or exon 12 if adapted) testing. No BM biopsy. Phlebotomies to Hct <45%. Low-dose ASA 75 mg/day. FBC every 2 weeks for 3 months, then monthly. Hospital consultations at 3, 6 and 12 months. peg- IFNα 90 μg every 1–2 week. Concomitant prescription of HU in case of proliferation. FBC every 2 weeks for 3 months, then monthly. Hospital consultations at 3 and 9 months. Ruxolitinib, 20 mg/day. Monthly blood examinations. Hospital consultation at 3 and 9 months. In university hospitals. Genotypic match, haplo>pheno-identical donors. Conditioning: Bu/Flu/ATG. FBC, SBP, se-EPO. Molecular tests for JAK2, CALR and MPL mutations. NGS in a subset based on availability of funding. BM biopsy for karyotyping. Phlebotomies and ASA. Follow every week to Hct <45%, then refer back to primary physician to maintain Hct. Review at tertiary centre every 6–12 months HU to be added to first line. Change regular review to tertiary centre at 2–3-month intervals for closer monitoring. In a small subset ruxolitinib. Otherwise, initiate search for an allogeneic donor for AHSCT peg-IFNα; follow-up at haematology out-patient clinic. HU, follow-up at same haematology out-patient clinic. Ruxolitinib not financed. Ruxolitinib if transformed into MF. Evaluation for possible AHSCT. At one of six university hospitals, Bu/Flu+ATG conditioning FBC, blood film, serum Epo. JAK2 mutation screen for all exons. Comprehensive metabolic panel, LDH, uric acid, BM examination, cytogenetic studies (NGS optional) Venesection + daily ASA for all patients. High-risk: HU if main objective is to prevent thrombosis peg-IFNα if intolerant or resistant to HU or non-thrombotic indication such as symptoms or increased venesection requirement. peg-IFNα for child-bearing age peg-IFNα reasonable alternative to HU in younger high-risk patients. peg-IFNα if intolerant or resistant to HU Bu for older age group. Ruxolitinib for post-PV MF or in the presence of drug-resistant symptomatic splenomegaly or intractable pruritus Only considered in the context of high-risk post-PV MF Ruxolitinib bridging not necessary Depends on clinical need. Stable PV: FBC frequency dictated by interval for venesection. Stable PV not needing venesection: FBC every 3 months and doctor visit every 6 months Post-AHSCT: according to transplant centre protocol The MPNs are comprised of polycythaemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). Originally suggested as an entity by Dameshek,1 and the subject of intense debate regarding their diagnosis in the ensuing decades, they are now firmly established molecular features by the ground-breaking reports on the Janus kinase 2 (JAK2)2, 4 and calreticulin (CALR)5 mutations. While clearly game-changing in the diagnosis of these disorders, they are of limited help in distinguishing between some clinical pictures, which can be similar between the subgroups at diagnosis, or in evaluating the course of disease, which can be notoriously fluctuating. Box 1 Case story (P. Hokland) A 53-year-old man has experienced intermittent headaches during the last 2 years prior to contacting his general practitioner (GP) after an old school friend he had not seen for 10 years described his face as ‘red as a tomato’. The GP confirms the latter, finds a hypertension of 165/105 mm Hg after 10 min in a supine position. In addition, she finds the spleen just palpable below the left curvature when the patient is positioned to the left and at peak inspiration. She finds the following: haemoglobin concentration of 11.2 mmoL/l (180 g/l), haematocrit level of 0.53, platelet count of 170 × 109 and leucocyte count of 9.1 × 109 with 82% neutrophils. Anamnestically, he has no competing conditions. He has a younger sister and a brother, who are both healthy. The GP telephones you and asks for advice. The primary baseline tests I would recommend from a haematological standpoint are JAK2 mutation panel and serum erythropoietin (Epo) level, as well as a blood film. I would also minimally recommend a biochemistry panel that includes renal function/electrolytes, liver enzymes, and serum lactate dehydrogenase (LDH) level. If possible, to broaden this, I would add serum ferritin, vitamin B12 and uric acid levels. As second-tier investigations, I would obtain a bone marrow (BM) biopsy for diagnostic and prognostic purposes,6 as well as an abdominal ultrasound to evaluate spleen size. Box 2 Questions for the panel (P Hokland) Question 1 (Q1): Please indicate what further diagnostic tools you advise her to employ in the present situation and whether these should be employed in primary care or at your institution. Please indicate the minimal clinical biochemistry evaluation at the first follow-up visit. Question 2 (Q2): Assuming that a diagnosis of PV is reached, please relate your preferred first-line therapy and how to and where the patients should be followed Question 3 (Q3): At 26 months after diagnosis at a scheduled control visit you find that first-line therapy has had limited effects. On the contrary, he has developed night sweats with increasing haematocrit, leucocyte and platelet values. Moreover, the spleen is now palpable ~6 cm (three fingerbreadths) below the left costal margin. What will constitute your second line of therapy? How and where should the patient be followed at this stage of disease? Question 4 (Q4): After 6 months it turns out that the second-line therapy has also failed. What treatment options are left at your centre? If these include an allogeneic haematopoietic stem cell transplantation (AHSCT), please I would recommend immediate venesection until a haematocrit level of <45% is attained, as well as oral aspirin 80 mg/day. As the patient is aged <60 years and has no history of thrombosis, no cytoreduction is indicated at present. In our centre, this patient would be followed closely in our specialised MPN clinic (every 2–3 weeks initially, then once stabilised, every 3 months) with initial weekly venesections until target is reached, followed by maintenance venesections as needed. If this patient is in a community hospital in our province, the same approach is taken, with more distanced follow-up appointments, although the treatment approach is the same. Payment structure in Canada is according to a universal healthcare plan. This coverage is paid for through taxes and individuals are not required to pay anything additional for most public healthcare services. Each province or territory has their own specific plan. I would first recommend performing a BM aspirate/biopsy to ensure no disease transformation, although unlikely if haematocrit still meets criteria for PV (however, development of ‘B’ symptoms and progressive leucocytosis/thrombocytosis are concerning for fibrotic transformation). Notwithstanding, the patient now has progressive disease with new-onset constitutional symptoms and worsening splenomegaly. Venesection and aspirin alone will no longer suffice to control these symptoms and cytoreductive therapy should be instituted. Hydroxycarbamide (hydroxyurea [HU]) would be the front-line choice. Interferon-α (IFNα) could also be considered but with recent production issues (difficulty obtaining) and potential toxicities, HU remains the first choice.8 Due to his younger age, busulfan (Bu) would not be considered a viable option here due to leukaemogenic potential.7 We would have access to any of these therapeutics, although as mentioned, standard IFNα has been difficult to obtain of late, and the pegylated formulation is not covered by the public drug insurance programme in our province (the patient would only have access if paid out-of-pocket, or if he/she had private insurance). I am assuming the patient has transformed to myelofibrosis (MF) if we are now talking about transplant. If failing HU, JAK inhibitor therapy would be the next line of therapy I would consider (ruxolitinib) for symptom control. Access is granted if patient exhibits symptomatic splenomegaly and is intermediate-2 or high risk according to International Prognostic Scoring System (IPSS) score. If risk stratification aligns the patient with a higher-risk category, I would also refer for AHSCT in parallel with symptom palliation.9 Our institution is a transplant centre and we receive referrals from across the province. Once the patient is referred and deemed to have a valid indication for transplant, the transplant team deploys the donor search and co-ordinates all procedures. While strictly higher-risk patients are referred, we have repeatedly been told by our transplant group that earlier referral and initiation of donor search is better, the reproach being that later-stage, more heavily complicated patients experience greater toxicity and less favourable outcomes. Therefore, I tend to refer as soon as the prognostic risk score dictates (the donor search would then be commenced at this stage as well), even if the patient is clinically well. Acceptable donors would include HLA-matched siblings or unrelated donors, with haploidentical donors also considered. Conditioning regimens used for MF at our institution generally consist of Bu-cyclophosphamide (Cy) or Bu-fludarabine (Flu). The physicians/team from the MPN clinic continue to follow the patient (in parallel with transplant team) until the time of transplant, and handle adjustment of medication and ‘day-to-day’ issues patients might be having that are not directly related to transplant. The Blood Diseases Hospital and Institute of Haematology, Chinese Academy of Medical Sciences and Peking Union Medical college is the unique national blood diseases specialised hospital in China. There are 795 beds only for blood diseases, and I am the director of the myelodysplastic syndromes (MDS) and MPN Centre, and the director of Hematologic Pathology Centre. I would confirm the diagnosis of PV with relevant tests, including full blood count with differential, uric acid, LDH, liver function tests, Epo level, serum iron and ferritin levels, BM aspiration with iron stain, BM biopsy with trichrome and reticulin stain, JAK2 V617F and JAK2 exon 12 mutations for JAK2 V617F-negative patients, abdominal ultrasound and assessment of symptom burden using the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS, MPN-10).6 All of the laboratory tests could be done in-house. Familial erythrocytosis exhibits both autosomal dominant and recessive Mendelian transmission. It is characterised by an absolute increase in red cell mass with accompanying raised haemoglobin and haematocrit levels in the absence of elevated platelets and white blood cell counts. As both of his younger sister and brother are healthy, then, I would not initially screen for familial erythrocytosis in the absence of any pre-existing personal or family history. On suspicion of a hereditary background, I would screen potential predisposition genes for suspicion familial erythrocytosis by whole-exome sequencing. We usually recommend such a patient to be referred to a specialised hospital with expertise in management of PV like my own institution. At presentation, aspirin, 100 mg daily, will be given to all patients with PV. If the patient is intolerant to aspirin, clopidogrel, 75 mg, daily, will be administered. Only red blood cell (RBC) apheresis, not venesection, which has been alternated by RBC apheresis in departments of blood transfusion, is covered by the government basic medical insurance in China, and consequently, venesection is used only in a few Chinese with PV. Conventional IFNα and HU are covered by Chinese basic medical insurance, so these cytoreductive agents are consequently recommended as the first choice by a Chinese expert consensus on diagnosis and treatment of PV and ET, including low-risk patients. Usually, conventional IFNα is recommended first for young (aged <60 years) or older patients without contraindications, for others HU is recommended. Patients with platelet counts of ≥ $$ \ge $$ 600 × 109/l or leucocyte counts of ≥ $$ \ge $$ 15 × 109/l would tend to receive a combination of IFNα and HU initially.10, 12 Generally, the initial dose of IFN is 3 × 106 iu, three times/week, and that of HU is 20 mg/kg/day. Treatment schedules will subsequently be adjusted by monitoring peripheral blood counts. Monitor response and signs/symptoms of disease progression (MPN-10) every 3 months in the out-patient by referral hospital (like my own institution) doctors, and in order to avoid the inconvenience of travel, a full blood count every month could be performed at the local hospital. The Chinese national health service is not a residence-based healthcare system, and there are no GP clinics, so patients are usually referred directly to hospitals. Usually, BM biopsy with trichrome and reticulin stain will be done to confirm whether the patient has progressed to post-PV MF. If diagnosis of post-PV MF is confirmed, ruxolitinib will be the first choice for the second-line therapy. The government basic medical insurance will pay 60% of these costs. The patient will then be monitored for response and dose adjustment in an out-patient setting every 1 month12 at the referral hospital. For patients who lack financial support, single drug IFNα or HU, or IFN combined with HU will be recommended. They, too, will be monitored for response and dose adjusted in an out-patient clinic every 2–3 months at the referral hospital. For MF, AHSCT is not recommended for patients aged >55 years.13 There are several ongoing clinical trials in China, including a phase III, multicentre, open-label, randomised study to evaluate the efficacy and safety of fedratinib compared to best available therapy in subjects with Dynamic IPSS (DIPSS), intermediate or high-risk PMF, post-PV MF, or post-ET MF and previously treated with ruxolitinib (No. FEDR-MF-002). At the present, in China, there are three new JAK–STAT signal pathway inhibitors, Jaktinib (No. ZGJAK006, No. ZGJAK017), TQ05105 (No. TQ05015-1-01) and LNK01002 (No. LNK-1002-01) that are all in ongoing clinical trials in China. Such clinical trials will be recommended to non-transplantable patients with MF. For AHSCT candidates, donor search for patients with DIPSS intermediate-2 or high risk and aged <60 years will be initiated after diagnosis of MF. We only recommend HLA-identical sibling donor transplant or an HLA-identical unrelated donor transplant for patients with MF. Now, transplants are performed only in six hospitals (like my own institution) with experts especially for management of MF patients’ transplant. In China the commonly preferred conditioning regimen include Bu3 + Cy, Flu + decitabine (Dac) ± total body irradiation (TBI)/thiotepa. As in many other countries, patients like the present one could be firstly managed by the GP and fully diagnosed by specialists in hospitals. In most cases, patients need the GP to refer them to specialists. Most of the haematologists in France are working in hospitals, where the health system allows everyone to be <100 km from a hospital. In the present case, we can suspect the existence of PV. In my hospital, before seeing the patient, we frequently ask the GP to identify (concomitant) secondary causes of polycythaemia like tobacco use and chronic hypoxic respiratory diseases. The GP can refer the patient to a pneumologist to identify an obstructive sleep apnea syndrome (we do not know his weight and height), which is frequently underestimated as cause of polycythaemia.14 Nevertheless, the diagnosis of PV will be assessed by a haematologist. For such patients, we give an appointment (with a MPN specialist) within 2 months after the initial solicitation. In case of later appointment, we can choose to accelerate the diagnostic process by asking the patient to meet a consultation nurse and have a blood examination performed before the specialist consultation.15 At the consultation, examination will be done again to assure the presence of the described symptoms and to look for erythromelalgia, aquagenic pruritus, palpable splenomegaly, or constitutive symptoms. A systematic blood examination will be made comprising blood film, CD34 count, plasma Epo level, and JAK2 V617F mutation testing. The laboratory of haematology will perform JAK2 exon 12 identification in case of negativity of JAK2 V617F and low Epo level. BM biopsy will only be done in case of double negativity, together with next-generation sequencing (NGS) analysis, cytogenetic analysis and progenitor cultures (search for spontaneous growth of burst-forming unit-erythrocyte [BFU-E] and colony-forming unit-megakaryocyte [CFU-MK] colonies), all done in our hospital.9 Given that we are dealing with a fairly young patient, without history of thrombosis and with isolated polycythaemia, I would solely prescribe venesection, as urgent treatment, as well as chronic therapy. In case of refusal (vein problems, needle fear, nurse constraints), my alternative will be the prescription of cytoreductive drugs such as HU or pegylated-IFNα (peg-IFNα). Nevertheless, the patient will have blood tests every 2 weeks at a local laboratory, the objective being to reach a haematocrit level of ≤45% (the nurse intervention will be automatic in case of venesection).16 A new consultation will be given at 3 months with his haematologist. In case of problems, clinicians are available on the telephone, the clinical nurse specialists and GP can also interact with patients. After 3 months, in case of tolerance and efficacy, new hospital appointments will be given at 6 and 12 months and followed by monthly local blood examinations. Of course, for this patient, I would prescribe low-dose aspirin 75 mg/day. For a patient diagnosed with a MPN, the disease will be reported by the GP to the National Social Security (NSS) system and all charges will be paid by it. In case of secondary resistance to venesections or progression despite them, the next treatment will be a discussion between the patient and the haematologist. As first drug, I would be more inclined to prescribe peg-IFNα for a young patient,17 initially 90 μg/week or per 2 weeks. Sometimes, in case of very high leucocyte or platelet counts, I frequently add HU to reduce myeloproliferation more rapidly during the first months, as peg-IFNα is frequently slow acting. I have observed that this drug is adapted to young patients and can really reduce myeloproliferation, constitutive symptoms and reduce splenomegaly within the first 6 months. My objective will be to obtain complete haematological response, or as a minimum, a haematocrit level of <45%. The differential diagnosis of the patient at this stage will be between progression of PV and evolution into secondary MF. I would prescribe a new blood test in hospital to assess the actual status of the MPN: blood film with focus on circulating immature cells and dacrocytes, a CD34 count, the LDH level, the JAK2 V617F allele burden. If findings suggest MF, I will perform a BM biopsy to verify diagnosis. In both MPN situations, the patient has been exposed to HU for less than a few months. Moreover, he is still young (aged <60 years). Consequently, HU will not be my choice of cytoreduction, because of the presentation of the patient (especially the constitutive symptoms and the splenomegaly). I will therefore prescribe ruxolitinib at 20 mg/day.18 We never perform AHSCT for PV, but will rather wait for evolution into secondary MF, and then only after (i) developed resistance or intolerance to both ruxolitinib and peg-IFNα, (ii) intermediate 2 or high-risk score according to DIPSS or, (iii) overt acute leukaemia (after induction therapy by intensive chemotherapy, like 3 + 7). AHSCT will be performed in a haematology intensive unit localised in a university hospital, like mine (with use of laminar flow ventilation). When AHSCT has been discussed and approved in our multidisciplinary meeting, brothers and sisters will be tested as potential geno-identical donors. In case of no match, children and parents will be tested as haploidentical donors before searching for anonymous donors as pheno-identical donors (national or international registries). The Flu-Bu-anti-thymocyte globulin (FB2-ATG) conditioning regimen will be prescribed, followed by infusion of cells and prescription of ciclosporin/mycophenolate mofetil (CsA/MMF) association to prevent graft-versus-host disease (GvHD).19 While it is very unlikely that patients in India will have a face described as ‘red as a tomato’, with the exception of a small subset who are fair skinned, severe polycythaemia will be apparent by examination of the palms, soles and a more purplish to cyanotic skin tone when severe. For this patient where a diagnosis of MPN is most likely, we would advise the primary physician to refer the patient to us or another tertiary centre, if possible, to do the baseline diagnostic evaluation. There is significant heterogeneity in access to high-end medical diagnostic and care in India, with state-of-the-art technology available in most metropolitan areas comparable to that available in any developed country, but for vast parts of the rural hinterlands only basic diagnostic tools are available at primary care centres.20, 21 While accurate national demographic data is not available it is reasonable to anticipate that a majority of close to 70% of the population living in rural areas are unlikely to have access to high-end molecular diagnosis. At our centre (not-for-profit private hospital) all patients have to pay for tests either through insurance or from out-of-pocket expenses. In addition to the full blood counts, we would do a baseline biochemistry evaluation that would include, but not be limited to, serum Epo, uric acid, renal and liver functions and rule out by appropriate tests secondary causes of polycythaemia. We would also do a BM aspirate and trephine and send samples for karyotyping, molecular tests for standard MPN mutation profile (JAK2, CALR, myeloproliferative leukaemia proto-oncogene, thrombopoietin receptor [MPL]) and if the patient's financial resources permit we would also send a sample for a baseline NGS panel. At our centre all these tests are done in-house, there are also a number of service providers in the country for molecular tests and NGS that makes it available for all secondary and tertiary centres in the country. With the exception of a few government hospitals in the main metropolitan areas where these molecular tests could be available free of cost, for the majority of private, for profit and not-for-profit healthcare centres they will have to be paid for by an insurance provider if available or as out-of-pocket expenses for the patient. We would initiate venesection, twice a week at the onset if required, to get the haematocrit level to <45%. We would start the patient on low-dose aspirin and ensure that we get his elevated blood pressure under control. Subsequently, we would see the patient once a week for 2–4 weeks until the haematocrit is under control and then refer him back to his primary physician to periodically check his haematocrit and do venesections, as and when required to maintain a target level of <45%. We would also ask the patient to visit us at intervals of between 6 months to a year to monitor progress. Some patients will opt to follow-up with us on a regular basis and visit us once every 2–3 months or more frequently as required. Most of interventions planned at this stage are feasible, even at primary care centres in the country, although for venesections they may need to go to a secondary level hospital. The cost of this therapy at this stage is affordable for all and will be available free of cost in any government run hospital. Considering that many patients have minimal symptoms, and some patients travel >500 km to a tertiary centre, it is not unusual for patients to be lost to follow-up or to follow-up at irregular intervals at the tertiary centre they were diagnosed at and in the absence accurate data it is estimated this would happen in close to 30% of diagnosed cases. At this point we would start the patient on therapy with HU and gradually increase the dose to a maximum of 2 g/day or stop at a dose tolerated or limited by leucopenia. All such patients we would be recommended to follow-up with us or at a tertiary centre at regular 2–3-month intervals (more frequently if required) to monitor disease progression closely. While this therapy can be accessed free of cost at a tertiary government hospital, many patients opt for treatment in private hospitals for perceived ease of access. The progressive nature of this patient's disease and possibility of having transformed or progressed to a secondary MF would warrant a complete re-evaluation of the disease status including repeat BM test, karyotyping and molecular analysis including an NGS panel. Considering the relatively young age of the patient, we would initiate a search for a suitable allogeneic stem cell donor including initiation of a matched unrelated donor (MUD) search. The preferred donor would be a fully HLA-matched related donor with a fully matched MUD being our next best option and finally a haploidentical family donor. MUD search and MUD donors can be accessed through multiple donor registries that exist in the country, most centres can also access donors via the National Marrow Donor Program (USA) and Deutsche Knochenmarkspenderdatei (Germany). An AHSCT, if warranted based on indication and absence of significant comorbidities would be done at our centre. Prior to transplant, if the patient has resources available, either insurance and/or ability to pay out-of-pocket, we will consider starting the patient on ruxolitinib as bridging therapy with the objective of improving the patient's performance status and reducing splenomegaly prior to transplant. However, in the absence of a generic molecule, as is the case with generic tyrosine kinase inhibitors for chronic myeloid leukaemia,22 ruxolitinib even with the expanded access programme support provided by the innovator is expensive and not accessible to the majority of patients. We would use a reduced toxicity Flu/Melphalan (Me) conditioning regimen with a peripheral blood stem cell graft. If a haploidentical transplant is considered, we would use a post-transplant Cy GvHD prophylaxis regimen. The Swedish Society for Haematology's working group for MPN has published care guidelines that are easily available for every practicing physician (available on-line at www.sfhem.se, not published in peer-review, but work is mandated by the Swedish authorities). I would ask the GP to evaluate smoking habits, the presence of microvascular symptoms or itching, and assess constitutional symptoms such as night sweats, involuntary weight loss or fatigue. Laboratory tests in the GP's office would include creatinine, electrolytes, uric acid, liver enzymes, glucose, lipids, ferritin, and serum Epo. Simultaneously, the patient should be referred to a haematology out-patient clinic either at a university hospital or, if more convenient, a local hospital with a haematology branch with a Department of Internal Medicine. The patient will be referred to the nearest hospital, i.e. Internal Medicine if closer than nearest haematology department. During the first visit blood will be sent for analysis of JAK2 V617F and exon 12 mutations by gene sequencing at a university hospital laboratory. Our national registry shows that BM biopsy is almost always done. A BM biopsy is performed in order to establish a diagnosis according to World Health Organisation (WHO) 2016. After a PV diagnosis the patent will be treated at a haematology out-patient clinic. In Sweden no private practice haematology exists. His GP will treat his hypertension. Swedish healthcare is provided by the regional government. A patient will pay at the most 180 Euros for clinic visits and treatments, and 220 Euros for medication